Gadolinium containing complexes formed with the ligands diethylenetriaminepentaacetic acid (DTPA) or 1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane (DOTA) provide complexes known as Magnevist™ and Dotarem™, respectively, which are approved for clinical applications. In their unmodified form, they are radiologically efficacious but non-specific agents suitable for the acquisition of MRI images of the circulatory system (the “blood pool”) and abnormalities therein. See Jacques, V., et al., Contrast Agents I, 221: 123-164 (2002) and Clarkson, R. B., Contrast Agents I, 221: 201-235 (2002). Most common contrast agents (CA) derive from modifications of DTPA and DOTA to endow them with specificity towards certain tissues and cells. See Jacques, V., et al., Contrast Agents I, 221: 123-164 (2002). In principle, high contrast and specificity is accessible with multivalent particles that contain multiple surface lanthanide complexes and multiple targeting groups to augment contrast and tissue specificity, respectively. See Woods, M., et al., Chem. Soc. Rev., 35(6): 500-511 (2006); Weissleder, R., et al., Nat. Biotechnol., 23(11): 1418-1423 (2005); and Caplan, M. R., et al., Ann. Biomed. Eng., 33(8): 1113-1124 (2005).
Silver or gold nanoparticles, are ideal for the preparation of multivalent constructs. Robust attachment on the surface of these metal particles is achieved through phosphine, amine, carboxylate, thiol, or thioether linkages. See Glomm, W. R., Journal of Dispersion Science and Technology, 26(3): 389-414 (2005) and Hostetler, M. J., et al., Current Opinion in Colloid & Interface Science, 2(1): 42-50 (1997).
Molecules, and chelating moieties in particular, can attach to the surface of Ag or Au nanoparticles through sulfur linkages via physi- and chemisorption. See Lavrich, D. J. et al., J. Phys. Chem. B, 102(18): 3456-3465 (1998) and Pederson, D. B., et al., J. Phys. Chem. A, 109(49): 11172-11179 (2005). The practice of binding thiols to these particular metals either in their bulk phases or as nanoparticles is very well developed. See Ulman, A., Chemical Reviews (Washington D.C.), 96(4): 1533-1554 (1996). Similarly extensive are the methods for producing nanoparticles that are highly monodisperse, which is important to ensure a uniform response when the agent is administered to an organism. See Brust, M., et al., Colloids and Surfaces, A: Physicochemical and Engineering Aspects, 202(2-3): 175-186 (2002) and Daniel, M.-C., et al., Chemical Reviews (Washington D.C.), 104(1): 293-346 (2004). The ultimate constructs consisting of surface derivatized metal particles are known as core-shell assemblies which are similarly monodisperse when the surface is of uniform thickness. Certain core-shell assemblies to be discussed are of potential importance as imaging agents for MRI. The colloidal assemblies discussed below are constructed of nanoparticulate and molecular components that are clinically approved, which may expedite the eventual approval of efficacious imaging agents that result from the proposed research.
In the early decades of the 20th century, colloidal gold was used to treat rheumatoid arthritis. See Salter, R. B., et al., Immune React. Exp. Models Rheum. Dis., Proc. Can. Conf. Res. Rheum. Dis., 4th, 165-173 (1972) and Tarsy, J. M., J. Lab. Clin. Med., 26: 1918-1924 (1941). In recent years, gold colloids have been used for immunodiagnostics and histology. See Daniel, M.-C., et al., Chemical Reviews (Washington D.C.), 104(1): 293-346 (2004). The uptake of thiols or disulfides from solution to form self-assembled monolayers (SAMS) on the surface of group 11 metals is of importance in catalysis, biomolecular sensing, and microscopy among other applications. The formation of thiol SAMS on gold and silver nanoparticles has been applied to form colloids as well as solid phases of cross-linked particles. See Brust, M., et al., Colloids and Surfaces, A: Physicochemical and Engineering Aspects, 202(2-3): 175-186 (2002) and Daniel, M.-C., et al., Chemical Reviews (Washington D.C.), 104(1): 293-346 (2004). In recent years, the solubility properties and methods for their manipulation have been detailed for these colloids. The potential of metal colloids for diagnostics and therapeutics has been recently mentioned. See Paciotti, G. F., et al., Drug Delivery, 11(3): 169-183 (2004); U.S. Patent Publication 20050175584; U.S. Patent Publication 20020192814; and Visaria, R. K., et al., Molecular Cancer Therapeutics, 5(4): 1014-1020 (2006).
Thiol (R—SH) and disulfide (R—SS—R) groups on compounds are employed to attach said compounds to metal and metal oxide surfaces. Those surfaces may be but are not limited to Ag, Au, Cu, Fe, FeO, Fe2O3, and Fe3O4. When thiols are employed as the attaching groups the attachment to metal may not be the sole reaction that occurs as thiols readily oxidize to form disulfide groups. The oxidation to form disulfide groups is undesirable when it results in the polymerization of the organic compounds that would otherwise attach to a metal surface to form a self-assembled monolayer (SAM). The polymerization of S—R—S groups results in a construct whose properties as a solute and as a contrast agent are difficult to control. Prior art shows that the complex [Gd(DTPA) dithiol] on a metal (M) particle forms a multilayer. See Debouttiere et al., Advanced Functional Materials, 16(18): 2330-2339 (2006).
The present invention is directed to overcoming these and other deficiencies in the art.